Cholecystokinin tetrapeptide effects on HPA axis function and elevated plus maze behaviour in maternally separated and handled rats

Deficits in the function of the hypothalamic-pituitary-adrenal (HPA) axis have been suggested to predispose to the development of depression and anxiety disorders. This is mirrored in the animal model "Maternal Separation (MS) where the stress of repeated separation of rat pups from the dam during early postnatal development results in long lasting alterations in HPA axis function. Cholecystokinin increases serum concentrations of stress axis hormones and might be involved in the dam-pup interaction in rats. Therefore, we hypothesized that adult animals, which had been separated daily (postnatal days (PND) 2-14) for 180 min (MS180) would differ in HPA axis responsiveness to an intravenous challenge dose of cholecystokinin tetrapeptide (CCK-4) compared to handled rats, separated for 15 min daily. The study explored the effects of intravenous CCK-4 on elevated plus maze behaviour and HPA axis hormones. MS 180 animals displayed reduced general activity but unaltered levels of open arm activity in the elevated plus maze. CCK-4 administration elevated general activity in the handled rats, while leaving MS 180 rats unaffected. MS 180 rats had increased baseline CRF mRNA expression in the paraventricular nucleus of the hypothalamus. When CRF mRNA was assessed in chronically catheter implanted and single housed rats, lower levels were found in the paraventricular nucleus of MS 180 animals compared to handled animals and this parameter was not affected by CCK-4 treatment. Adrenocorticotropin concentrations in serum were equal in MS 180 and handled rats and unaffected by CCK-4. Corticosterone serum concentrations were lower in saline treated MS 180 rats compared to saline treated handled rats. CCK-4 injection raised serum corticosterone in MS 180 rats to levels equal to the handled rats, while leaving handled rats unaffected. We suggest that the lower levels of hypothalamic CRF mRNA and serum corticosterone concentrations in MS 180 rats might be due to the experimental set-up with chronic venous catheter implants and single housing. In conclusion, this study supports the hypothesis of elevated CCK sensitivity in separated rats as measured by corticosterone changes thus adding to the existing literature reporting early life stress having long-term impact on HPA axis function. (c) 2005 Published by Elsevier B.V.